Training B cells to generate broadly neutralizing HIV antibodies

Human immunodeficiency virus (HIV), the virus that causes AIDS, continues to spread through the human population. In 2015 37 million people were living with HIV and 2.1 million people got newly infected, while 1.1 million people died of AIDS in the same year. The worldwide benefit of an effective HIV vaccine is therefore undisputed, but such a vaccine is not yet within reach. The correlates of protection of most licensed antiviral vaccines are neutralizing antibodies. Neutralizing HIV antibodies target the only protein on the outside (the “envelope”) of the virus: the “envelope protein”. The induction of any neutralizing antibodies by HIV vaccines has proven to be a major challenge. I have recently overcome that hurdle by creating recombinant HIV envelope proteins that adequately mimic the native envelope protein present on the virus. We have shown that such proteins can induce neutralizing antibodies against natural HIV viruses, something that has not been achieved by previous HIV vaccine candidates. However, important challenges still remain. Since HIV is highly variable it will be necessary to induce neutralizing antibodies that can cope with that variation, i.e. “broadly neutralizing antibodies”, and that is the goal of this project. A subset of HIV infected individuals generates broadly neutralizing antibodies and these individuals can form the templates for vaccine design. In these patients, HIV broadly neutralizing antibodies are the product of a cat-and-mouse game between virus and immune system. My hypothesis is that we can mimic this cat-and-mouse game by vaccination and will be able “to train” the immune system to induce broadly neutralizing antibodies. In order to do so, we will select HIV infected patients from the Amsterdam Cohort Studies on HIV/AIDS that have generated exceptionally broad and potent neutralizing antibodies. We will then select the evolving envelope protein sequences from these patients, generate recombinant envelope proteins from those sequences and use these sequences for sequential vaccination strategies. This will be complemented with a number of high-tech iterative and structure-based vaccine design approaches. The overall goal is to mimic by active vaccination the cat-and-mouse game that played out in these patients and resulted in the induction of broadly neutralizing antibodies. My expertise in engineering recombinant HIV envelope proteins and studying neutralizing antibodies, puts me in an excellent position to perform the proposed studies and achieve my goal.